Investigating how the attributes of self-associated drug complexes influence the passive transport of molecules through biological membranes.
Investigating how the attributes of self-associated drug complexes influence the passive transport of molecules through biological membranes.
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DOI：
10.1016/j.ejpb.2016.03.002
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发表时间：
2016-05
期刊：
影响因子：
--
通讯作者：
Jones SA
中科院分区：
文献类型：
--
作者：
Inacio R;Barlow D;Kong X;Keeble J;Jones SA
关于药物自缔合如何影响人体吸收，人们知之甚少。本研究提出了两种疏水膜以及一系列含有不同类型丁卡因聚集体的溶液，旨在了解超分子聚集体形成的属性如何影响被动膜运输。数据显示，与非质子化和质子化药物微粒混合物的溶液相比，非质子化形式的丁卡因水溶液表现出显着更高（p < 0.05）的被动膜转运（例如，通过皮肤的转运分别为 0.96 ± 0.31 μg cm−2 min−1 和 1.59 ± 0.26 μg cm−2 min−1）。然而，尽管药物转运速率提高且膜分区更好，但与富含电离微生物的溶液相比，电离分子的膜渗透滞后时间明显更长（p < 0.05）。在传输研究中应用于膜顶端表面的溶液的分析表征表明，具有较小表面电荷的较大丁卡因聚集体导致较长的滞后时间。这些大的聚集体表现出更广泛的分子间键合，因此，表明未电离物质形成紧密结合的药物聚集体的倾向增强，导致膜渗透的延迟。
Relatively little is known about how drug self-association influences absorption into the human body. This study presented two hydrophobic membranes with a series of solutions containing different types of tetracaine aggregates with the aim of understanding how the attributes of supramolecular aggregate formation influenced passive membrane transport. The data showed that aqueous solutions of the unprotonated form of tetracaine displayed a significantly higher (p < 0.05) passive membrane transport compared to solutions with mixtures of the unprotonated and protonated drug microspecies (e.g. transport through the skin was 0.96 ± 0.31 μg cm−2 min−1 and 1.59 ± 0.26 μg cm−2 min−1 respectively). However, despite an enhanced rate of drug transport and a better membrane partitioning the unionised molecules showed a significantly longer (p < 0.05) lag time to membrane penetration compared solutions rich in the ionised microspecies. Analytical characterisation of the solutions applied to the apical surface of the membranes in the transport studies showed that larger tetracaine aggregates with smaller surface charge gave rise to the longer lag times. These large aggregates demonstrated more extensive intermolecular bonding and therefore, it was suggest that it was the enhanced propensity of the unionised species to form tightly bound drug aggregates that caused the delay in the membrane penetration.